This invention is directed to a process for preparing N6-substituted adenosine derivatives, to intermediates useful therefor and to methods of preparing these intermediates.
N6-substituted adenosine derivatives, as exempliified by [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3 H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide, are useful as a cardiovascular agents, more particularly as antihypertenisive and anti-ischemic agents, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. See U.S. Pat. Nos. 5,364,862 and 5,561,134 and International Patent Application No. PCT/US97/11320.
Methods of preparing these compounds and intermediates thereto are disclosed in U.S. Pat. Nos. 5,364,862 and 5,561,134 and Internationial Patent Application Nos. PCT/US97/11320, PCT/US97/15729 and PCT/US97/21439.
This invention is directed to a process for preparing an N-protected N6-substituted adenosine compound of formula 
wherein
P is a nitrogenl protecting group;
Q is CH2 or O;
T is 
xe2x80x83or R3Oxe2x80x94CH2;
X is a straight or branched chain alkylene, cycloakylyene or cycloalkenylene group;
Y is NR4, O or S;
a=0 or 1;
Z is of the formula 
Z1 is N, CR5, (CH)m-CR5 or (CH)m-N, m being 1 or 2;
Z2 is N, NR6, O or S;
n is 0 or 1;
R1, R2, R3, R4, R5 and R6 are independently H, alkyl, aryl or heterocyclyl;
R7 and R8 are independently H, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, or aryloxycarbonyl; or R7 and R8 together may form 
xe2x80x83where Rc is hydrogen or alkyl, 
xe2x80x83where Rd and Re are independently hydrogen, or alkyl, or Rd and Re together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and
Ra and Rb are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl, this process comprising reacting a 4-N-protected-2,3,4-triaminopyridine compound of formula 
with a formic acid derivative.
The process of the present invention offers improved yields, purity, ease of preparation and/or isolation of intermediates and final product, and more industrially useful reaction conditions and workability over previously disclosed methods of preparation.
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, have the following meanings:
xe2x80x9cAcylxe2x80x9d means a straight or branched alkyl-Cxe2x95x90O group. xe2x80x9cThioacylxe2x80x9d means a straight or branched alkyl-Cxe2x95x90S group. Preferred acyl and thioacyl groups are lower alkanoyl and lower thioalkanloyl having from 1 to about 6 carbon atoms in the alkyl group.
xe2x80x9cAlkylxe2x80x9d means a saturated aliphatic hydrocarbon group which may be straight or branched and has 1 to about 20 carbon atoms in the chain. Preferred alky groups may be straight or branched and has 1 to about 10 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain.
xe2x80x9cLower alkylxe2x80x9d means an alkyl group having 1 to about 6 carbons.
xe2x80x9cCycloalkylxe2x80x9d means an aliphatic ring having 3 to about 10 carbon atoms in the ring. Preferred cycloalkyl groups have 4 to about 7 carbon atoms in the ring.
xe2x80x9cCarbamoylxe2x80x9d means an 
group. Alkylcarbamoyl and dialkylcarbamoyl means that the nitrogen of the carbamoyl is substituted by one or two alkyl groups, respectively.
xe2x80x9cCarboxylxe2x80x9d means a COOH group.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-O, group in which xe2x80x9calkylxe2x80x9d is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkyl group, as previously described, substituted by an alkoxy group, as previously described.
xe2x80x9cAlkoxycarbonyl means an alkoxy-Cxe2x95x90O group.
xe2x80x9cAralkylxe2x80x9d means an alkyl group substituted by an aryl radical, wherein xe2x80x9carylxe2x80x9d means a phenyl or naphthyl. xe2x80x9cSubstituted aralkylxe2x80x9d and xe2x80x9csubstituted arylxe2x80x9d means that the aryl group, or the aryl group of the aralkyl group is substituted with one or more substituents which include alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl or carbamoyl.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkyl-O-Cxe2x95x90O group.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-O-Cxe2x95x90O group.
xe2x80x9cCarbalkoxyxe2x80x9d means a carboxyl substituent esterified with an alcohol of the formula CnH2n+1OH, wherein n is from 1 to about 6.
xe2x80x9cHalogenxe2x80x9d (or xe2x80x9chaloxe2x80x9d) means chlorine (chloro), fluorine (fluoro), bromine (bromo) or iodine (iodo).
xe2x80x9cHeterocyclylxe2x80x9d means about a 4 to about a 10 membered ring structure in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O or S. Heterocyclyl may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated. Preferred heterocyclyl groups include pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinoliniyl, quinazolinyl. imidazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, benzothiazolyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and morphonlinyl groups.
xe2x80x9cSubstituted heterocyclylxe2x80x9d means that the heterocyclyl group is substituted by one or more substituents wherein the substituents include alkoxy, alkylainino, aryl, carbalkoxy, carbamoyl, cyano, halo, heterocyclyl, trihalomethyl, hydroxy, mercaptyl, alkylmercaptyl or nitro.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl group substituted by a hydroxy group. Hydroxy lower alkyl groups are preferred. Exemplary preferred groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.
xe2x80x9cNitrogen protecting groupxe2x80x9d means an easily removable group which is known in the art to protect an amino (group against undesirable reaction during synthetic procedures and to be selectively removable. The use of N-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, CF, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. Representative N-protecting groups include sulfonainides such as methanesufonyl (Ms), trifluoromethanesulfonyl (Tf), benzenesulfonyl (or pheniylsuilfonvyl), p-toluenesulfonyl (Ts), p-methoxybenzenesulfonyl, phenacylsulfonyl, and the like; carbamates such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethyloxycarbonyl (Teoc), tert-butoxycarbonyl (Boc), and the like; amides such as formyl, acetyl, benzoyl, trifluoroacetyl, and the like; N-alkyl derivatives such as benzyl; and N-phosphinyl derivatives such as diphenylphosphinoyl.
In a specific embodiment, the term xe2x80x9caboutxe2x80x9d or xe2x80x9capproximatelyxe2x80x9d means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
The preparation of N6-substituted adenosine derivatives of formula (1) wherein X1, X2, X, Y, a, Z, P, Q, T, R7 and R8, are defined above is outlined in Scheme 1. 
As shown in the foregoing Scheme 1, reaction of the 2,4-dihalo-3-nitropyridine compound (II) and the N-protected amine (III) provides the 2-halo-3-nitro-4-N-protected aminopyridine compound (IV). The reaction is carried out in the presence of an alkoxide such as potassium tert-butoxide or potassium tert-amylate, and the like; an inorganic carbonate base such as potassium carbonate; a metal hydride base such as sodium or potassium hydride; an alkyllithium base such as butyllithium; or a fluoride base such as potassium fluoride. When weaker bases such as potassium carbonate or potassium fluoride are utilized, a crown ether such as 18-crown-6, or a phase transfer catalyst, such as tetrabutyl ammonium bromide may be added to achieve a reasonable rate of conversion. The reaction is carried out in an etheral solvent such as tetrahydrofuran, tert-butyl methyl ether, and the like; an aromatic hydrocarbon solvent such as toluene; or in a polar aprotic solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, and the like at a temperature of from about ambient temperature to the reflux temperature of the solvent.
The reaction is preferably accomplished using potassium tert-butoxide in tetrahydrofuran) at about 65xc2x0 C. The product is preferably purified by washing with methanol and heptane.
Alternatively, a metalated version of the protected amine (III) of formula P-NM-X-(Y)a-Z. where M is a metal cation such as Li may be used, in which case use of additional base is unnecessary.
The 2-halo-3-nitro-4-N-protected aminopyridine compound (IV) is then reacted with the protected dihydroxyaminocyclopentane compound (V) in the presence of an inorganic bicarbonate base, such as potassium bicarbonate; a tertiary or aromatic amine base such as 4-methylmorpholiine; an alkoxide such as potassium tert-butoxide or potassium tert-amylate, and the like; an inorganic carbonate base such as potassium carbonate; a metal hydride base such as sodium or potassium hydride; an alkyllithium base such as butyllithium; or a fluoride base such as potassium fluoride, in an ester solvent such as ethyl acetate; an etheral solvent such as tetrahydrofuran, tert-butyl methyl ether, and the like; an aromatic hydrocarbon solvent such as toluene; or a polar aprotic solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, and the like, at a temperature of from about ambient temperature to the reflux temperature of the solvent to form the 4-N-protected-2,4-diamino-3-nitiopyridine compound (VI). The reaction is preferably accomplished using potassium carbonate in ethyl acetate at about 80xc2x0 C.
The protected dihydroxyaminocyclopenitane compound (V) may be utilized as the free base, or as the acid addition salt. Preferred acid addition salts are the trifluoroacetate or benzoate salts.
The reduction of the 4-N-protected-2,4-diamito-3-iiitropyridine compound (VI) to form the 4-N-protected-2,3,4-triiaminopyridine compound (VII) is accomplished using methods well known in the art for the reduction of aromatic nitro compounds such as catalytic hydrogenation using a transition metal catalyst such as platinum. The reduction is also accomplished using a metal such as zinc, iron or tin in the presence of a proton source such as ammonium acetate. Solvents are generally alcohols, or mixtures of non-protic organic solvents such as ethyl acetate or toluene and an alcohol such as methanol. The reduction is preferably accomplished by catalytic hydrogeniationi at about 50 psi of hydrogen in the presence of platinum on carbon, in a mixture of ethyl acetate and methanol at room temperature.
The 4-N-protected-2,3,4-triiaminopyridine compound (VII) is then converted to the N-protected N6-substituted adenosine derivative (VIIl) by a reaction with a derivative of formic acid, such as triethyl orthoformate, diethoxymethyl acetate or formamidine acetate, and the like, in a polar aprotic solvent such as dimethylformamide; a higher boiling alcohol such as n-butanol, an ester such as n-butyl acetate; an anhydride suich as acetic anhydride, or an aromatic hydrocarbon such as toluene. Alternatively, the reagent itself (e.g. triethylorthoformate) can be used as the solvent for this reaction. The reaction is optionally catalyzed by an acid such as hydrochloric acid or p-toluenesulfonic acid. The reaction is accomplished at a temperature of from about ambient temperature to the reflux temperature of the solvent. Preferred reaction conditions are triethyl orthoformnate in acetic anhydride at about 120xc2x0 C.
Removal of the amine protecting group P is accomplished using reagents known in the art for the removal of nitrogen protecting groups. When P is sulfonamido, such as p-toluenesulfonyl, the protecting group is cleaved using a strong acid, such as methanesulfonic acid. hydrochloric acid, trifluoroacetic acid, and the like, or a strong Lewis acid, such as trimethylsilyl trifluoromethanesulfonate in a polar protic solvent such as acetic acid, trifluoroacetic acid, water and the like. A cation scavenger such as thioanisole generally is also employed, resulting in increased purity of the final product. In a preferred aspect of the foregoing process, the groups R7 and R8 together form the dimethyl acetonide. in which case the strongly acidic conditions described above for the removal of P typically also result in hydrolysis of the acetonide. Preferred conditions for removal of the nitrogen protecting group P are trimethylsilyl trifluoroacetate with thioanisole in trifluoroacetic acid at about 70xc2x0 C.
Alternatively, the tosyl group can be selectively removed by a reductive process using metals such as lithium, sodium, sodium-mercury couple, magnesium and the like. For lithium and sodium, ammonia is typically used as the solvent (dissolving metal reduction). Magnesium reduction is generally carried out in an alcohol such as methanol. The tosyl group might also be removed with a hydride reagent, such as lithium triethylborohydride in an aprotic solvent such as THF, or electrolytically.
In the event that the nitrogen protecting group P is selectively removed, the groups R7 and R8 are then removed using techniques known in the art forremoval of hydroxyl protecting grotups. When R7 and R8 together form the dimethyl acetonide, the acetonide is hydrolyzed usinig an acid such as hydrochloric acid or trifluoroacetic acid, in a protic solvent such as water or an alcohol; or an organic solvent such as tetrahydrofuran can also be used. Acetonide hydrolysis is preferably accomplished usinig a mixture of aqueous concentrated hydrochloric acid and tetrahydrofuran at a temperature ranging from ambient temperature to about 35xc2x0 C.
In a preferred aspect of the foregoing process,
Q is CH2;
T is 
X is a straight or branched chain alkylene;
a=0;
Z is 
Z1 is N, CR5, (CH)m-CR5 or (CH)m-N, m being 1 or 2;
Z2 is N, NR6, O or S; n is 0 or 1;
R1, R2, R3, R4, R5 and R6 are independently H or alkyl;
R7 and R8 are independently hydrogen or alkyl, or R7 and R8 together may form 
where Rd and Re are independently hydrogen or alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and
Ra and Rb are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl.
In a more preferred aspect of the foregoing process, P is selected from the group consisting of sulfonamides, carbamates, amides, N-alkyl derivatives and N-phosphinyl derivatives.
In a still more preferred aspect of the foregoing process, P is a sulfonamide derivative.
In a still yet more preferred aspect of the foregoing process, P is o-toluenesulfonyl.
A process for preparing [1S-[1xcex1,2xcex2,3xcex2,4xcex1(S*)]]-4-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl]amino]-3 H-imidazo[4,5-b]pyrid-3-yl]N-ethyl 2,3-dihydroxycyclopentanecarboxamide (XV) is shown in Scheme 2. 
As shown in the foregoing Scheme 2,2,4-dihalo-3-nitropyridine (II) (X1=F, X2=Cl or F) is reacted with the (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzesulfonamide compound (IX) to form the (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-halo-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide compound (X) (X2=Cl or F).
When Pxe2x80x2 is H, the reaction is performed by deprotonation of the secondary amine by reaction with base, preferably potassium tert-butoxide in tetrahydrofuran at a temperature of about 0xc2x0 C. to about ambient temperature, followed by addition of the 2,4-dihalo-3-nitropyridine compound and heating at about 65xc2x0 C. When Pxe2x80x2 is Li, no additional base is required and the reaction of (II) and (IX) is preferably performed in refluxing 1-methyl-2-pyrrolidinone or toluene.
In one preferred aspect of the foregoing, the 2,4-dihalo-3-nitropyridine compound (II) is 2,4-difluoro-3-nitropyridine, which is prepared by reaction of 2,4-diclhoro-3-nitropyridine with a nucleophilic fluoride reagent, preferably KF. Incomplete reaction of 2,4-dichloro-3-nitropyridine with the nucleophilic fluoride reagent results in formation of a mixture of 2,4-difluoro-3-nitropyridine and 2-chloro-4-fluoro-3-nitropyridine. Use of this mixture for reaction with the (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfoniamide, compound (IX), results in formation of the (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-halo-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide, compound (X), wherein halo is a mixture of Cl and F.
The (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-halo-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide, compound (X), is then reacted with 3aR-[3axcex1,4xcex1, 6a,6axcex1]-6-amino-N-ethyltetrahydro-3,3-dimethyl-2,4-dioxabicyclo [3.3.0]octan-8-carboxamide, benzoate (XI), to form [3aR-[3axcex1,4xcex1, 6a(R* ),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (XII). The reaction is preferably accomplished using excess alkoxide base, preferably potassium carbonate, at about 80xc2x0 C. in an organic solvent such as ethyl acetate or 1-methyl-2-pyrrolidinone. 1-methyl-2-pyrrolidinone is the preferred solvent when halo is a mixture of Cl and F. The preparation of 3aR-[3axcex1,4xcex1, 6a,6axcex1]-6-amino-N-ethyltetrahydro-3,3-dimethyl-2,4-dioxabicyclo[3,3,0]octane-8-carboxamide, benzoate is described in U.S. Pat. Nos. 5,808,093, 5,670,649 and 5,684,159, the contents of which are hereby incorporated herein by reference.
Reduction of [3aR-[3axcex1,4xcex1, 6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (XII) to form [3aR-[3axcex1,4xcex1, 6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (XIII) is then accomplished as described in Scheme 1 above, preferably by catalytic hydrogenation at about 50 to about 55 psi of hydrogen in the presence of catalytic platinum on carbon in a mixture of ethyl acetate and methanol at about ambient temperature.
Cyclization of [3aR-[3axcex1,4xcex1,6a(R*),6xcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (XIII) to form [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (XIV) is then accomplished as described in Scheme 1 above.
Conversion of [3aR-[3axcex1,4xcex1, 6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-1imidazo[4,5-b]pyrid-3-yl]N-ethyltetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide (XIV) to [1S-[1xcex2,2xcex2,3xcex2,4xcex2(S*)]]-4-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl 2,3-dihydroxycyclopentanecarboxamide (XV) is accomplished by the simultaneous or sequential removal of the toluenesulfonyl group and the dimethyl acetonide as described in Scheme 1 above.
Selective removal of the toluenesulfonyl group is preferably accomplished using magnesium metal in a mixture of methanol and toluene at about 40xc2x0 C. or using a hydride reagent such as lithium triethylborohydride in tetrahydrofuranat about 0xc2x0 C. The dimethyl acetonide is then hydrolyzed using an acid such as hydrochloric acid or trifluoroacetic acid, in a protic solvent such as water or an alcohol or an organic solvent such as tetrahydrofuran. Acetonide hydrolysis is preferably accomplished using a mixture of aqueous concentrated hydrochloric acid and tetrahydrofuran at ambient temperature to about 35xc2x0 C.
Simultaneous removal of the toluenesulfonyl group and hydrolysis of the acetonide is accomplished using a strong acid, such as methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, and the like, or a strong Lewis acid. such as trimethylsilyl trifluoromethanesulfonate in a polar protic solvent such as acetic acid, trifluoroacetic acid, water and the like. A cation scavenger such as thioanisole generally is also employed, resulting in increased purity of the final product. Simultaneous removal of the toluenesulfonyl group and the dimethyl acetonide is accomplished by heating a mixture of [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-7-[[1-[3-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and trimethylsilyl trifluoroacetate in trifluoroacetic acid/toluene at about 70xc2x0 C. or by heating a mixture of [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-]1,3-dioxole-4-carboxamide, methanesulfonic acid and thioanisole in trifluoroacetic acid at about 85xc2x0 C.
In another aspect, this invention is directed to a process for preparing [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide comprising
(i) reacting (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide with 3aR-[3axcex1,4xcex1,6a,6axcex1]-6-amino-N-ethyltetrahydro-3,3-dimethyl-2,4-dioxabicyclo[3.3.0]octan-8-carboxamide, benzoate to form [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide,
(ii) reducing the [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-yl amino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide prepared in step (i) to form [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and
(iii) reacting the [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide prepared in step 2 above with an orthoformate ester, formamidine acetate or dimethylformamide dimethyl acetal, wherein steps (i)-(iii) are performed in a concatenated fashion without purification of the intermediate compounds, [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide.
For example, (R)-N-[1-[-chlorothien-2-yl)methylpropyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide and 3aR-[3axcex1,4xcex1,6a,6axcex1]-6-amino-N-ethyltetrahydro-3,3-dimethyl-2,4-dioxabicyclo [3.3.0]octan-8-carboxamide, benzoate and potassium carbonate are heated in ethyl acetate to form an ethyl acetate solution of [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. The ethyl acetate solution is washed with water and brine to remove water-soluble impurities and then the ethyl acetate solution is diluted with methanol, a platinum catalyst is added and the mixture is hydrogenated under about 50 psi of hydrogen to give a solution in ethyl acetate/methanol of [3aR-[3axcex1,[4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. The catalyst is filtered off, the filtrate is concentrated, and triethyl orthoformate and acetic anhydride are added to the crude [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl [4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide. Heating of the mixture effects conversion to [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, which is isolated by crystallization, preferably using 2-propanol.
In another aspect, this invention is directed to a process for preparing (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-)halo-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide, wherein halo is Cl or F, comprising
(i) reacting 2,4-dichloro-3-nitropyridine with a fluorinating agent to form 2,4-difluoro-3-nitropyridine or a mixture of 2,4-difluoro-3-nitropyridine and 2-chloro-4-fluoro-3-nitropyridine and
(ii) reacting the product of step (i) with (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt or (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide, wherein steps (i) and (ii) are performed in a concatenated fashion without isolation of the product of step (i).
For example, heating a mixture of 2,4-dichloro-3-nitropyridine with KF and catalytic tetrabutylammonium bromide in toluene or toluene/1-methyl-2-pyrrolidinone results in the formation of a solution of 2,4-difluoro-3-nitropyridine. (R)-N-[1-[(3-chlorothien-2-yl)inethyl]propyl]-4-methylbenzenesulfonamide lithium salt is then added to the solution and the mixture is heated to effect conversion to the (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzesulfonamide, which is isolated by crystallization, preferably by aqueous extraction of the reaction mixture followed by addition of a hydrocarbon solvent such as heptane to the organic solution.
In another aspect of the foregoing process, excess KF is utilized, which acts as the fluorinating agent in the first step and the base in the second step, thereby making it possible to utilize (R)-N-(1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide rather than the lithium salt.
In another aspect, this invention is directed to a process for preparing [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide comprising
(i) reacting 2,4-diclhoro-3-nitropyridine with a fluorinating agent to form 2,4-difluoro-3-nitropyridine,
(ii) reacting the 2,4-difluoro-3-nitropyridine with (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt or (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide to form (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonylamide,
(iii) reacting the (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide with 3aR-[3axcex1,4xcex1,6a,6axcex1]-6-amino-N-ethyltetrahydro-3,3-dimethyl-2,4-dioxabicyclo [3.3.0)octan-8-carboxamide, benzoate to form [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-1-cyclopenta-1,3-dioxole-4-carboxamide,
(iv) reducing the [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide prepared in step (i) to form [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and
(v) reacting the [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide with an orthoformate ester, formamidine acetate or dimethylformamide dimethyl acetal wherein steps (i)-(v) are performed in a concatenated fashion without purification of the intermediate compounds 2,4-difluoro-3-nitropyridine, (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-halo-3-nitropyrid-4-yl)-4-methylbenzesulfonamide, [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-4-[[1-[(3-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide and [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl)propyl][4-methylbenzenesulfonyl]amino]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide, wherein the concatenation is effected by combining the concatenated processes described above.
In another aspect, this invention is directed to a compound of formula (XVI) 
wherein
A is NH2 or NO2;
P is a nitrogen protecting group;
W is Cl, F or a group of formula 
Q is CH2 or O;
T is 
xe2x80x83or R3Oxe2x80x94CH2;
X is a straight or branched chain alkylene, cycloalkylene or cycloalkylene group;
Y is NR4, O or S;
a=0 or 1; 
Z is of the formula
Z1 is N, CR5, (CH)m-CR5 or (CH)m-N, m being 1 or 2;
Z2 is N, NR6, O or S;
n is 0 or 1;
R1, R2, R3, R4, R5 and R6 are independently H, alkyl, aryl or heterocyclyl;
R7 and R8 are independently H, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, or aryloxycarbonyl, or R7 and R8 together may form 
xe2x80x83where Rc is hydrogen or alkyl, 
xe2x80x83where Rd and Re are independently hydrogen, alkyl, or Rd and Re together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and
Ra and Rb are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, tilloalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl, which compound is a useful intermediate in the preparation of N-protected N6-substituted adenosine compounds using the processes described herein.
Preferred compounds have formula (XVI) wherein P is selected from sulfonamides, carbamates, amides, N-alkyl derivatives and N-phosphinyl derivatives.
More preferred compounds have formula (XVI) wherein P is sulfonamido.
Still more preferred compounds: have formula (XVI) wherein
P is sulfonamido;
Q is CH2; 
T is R2 
X is a straight or branched chain alkylene;
a=0;
Z is 
Z1 is N, CR5, (CH)mxe2x80x94CR5 or (CH)m-N, m being 1 or 2;
Z2 is N, NR6, O or S, n being 0 or 1;
R1, R2, R5 and R6 are independently H or alkyl;
R7 and R8 are alkyl, or R7 and R8 together may form 
xe2x80x83where Rd and Re are independently hydrogen or alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and
Ra and Rb are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl.
Representative still more preferred compounds include, but are not limited to 3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3-nitropyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide: [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[4-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]-3-aminopyrid-2-ylamino]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide; and [3aR-[3axcex1,4xcex1,6a(R*),6axcex1]]-6-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl][4-methylbenzenesulfonyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl]N-ethyl tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-carboxamide.